- Co-immobilized Phosphorylated Cofactors and Enzymes as Self-Sufficient Heterogeneous Biocatalysts for Chemical Processes
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Enzyme cofactors play a major role in biocatalysis, as many enzymes require them to catalyze highly valuable reactions in organic synthesis. However, the cofactor recycling is often a hurdle to implement enzymes at the industrial level. The fabrication of heterogeneous biocatalysts co-immobilizing phosphorylated cofactors (PLP, FAD+, and NAD+) and enzymes onto the same solid material is reported to perform chemical reactions without exogeneous addition of cofactors in aqueous media. In these self-sufficient heterogeneous biocatalysts, the immobilized enzymes are catalytically active and the immobilized cofactors catalytically available and retained into the solid phase for several reaction cycles. Finally, we have applied a NAD+-dependent heterogeneous biocatalyst to continuous flow asymmetric reduction of prochiral ketones, thus demonstrating the robustness of this approach for large scale biotransformations.
- Velasco-Lozano, Susana,Benítez-Mateos, Ana I.,López-Gallego, Fernando
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Read Online
- Use of hydrophobic bacterium Rhodococcus rhodochrous NBRC15564 expressed thermophilic alcohol dehydrogenases as whole-cell catalyst in solvent-free organic media
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The hydrophobic bacterium Rhodococcus rhodochrous NBRC15564 was employed as a whole-cell biocatalyst to examine its potential for bioconversion in solvent-free organic media. The genes encoding two different thermostable alcohol dehydrogenases (ADHTt1 and ADHTt2) of Thermus thermophilus HB27 were expressed in R. rhodochrous cells. To inactivate indigenous mesophilic enzymes in R. rhodochrous, transformant cells were heated at 70 C for 10 min. Heat-treated hydrophobic wet cells were used for the bioconversion of 2,2,2-trifluoroacetophenone (TFAP) to α-(trifluoromethyl) benzyl alcohol (TFMBA) as a model reaction with ADHTt1. NADH, which was supplied in aqueous solution, was regenerated by converting cyclohexanol to cyclohexanone by ADHTt2. All reactions were performed by suspending heat-treated cells in solvent-free organic media consisting of 3.7 M TFAP and 4.8 M cyclohexanol (1:1, v/v ratio) at 60 C. When 800 mg heat-treated R. rhodochrous cells were dispersed in 2 mL of solvent-free organic media (400 mg cells/mL), the product concentration reached about 3.6 M TFMBA by 48 h with a total NADH turnover number of approximately 900. The overall productivity was 190 mol TFMBA/kg cells/h.
- Hibino, Aiko,Ohtake, Hisao
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Read Online
- Assessment of headspace solid-phase microextraction (HS-SPME) for control of asymmetric bioreduction of ketones by Alternaria alternata
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The aim of this study was to assess the effectiveness of headspace solid-phase microextraction (HS-SPME) compared to liquid–liquid extractions using with methylene chloride (CH2Cl2) for control of fungal biotransformation of ketones of varying volatility. The proposed method was successfully applied. The best way to extract all the components of the mixture (alcohols, aldehydes) in quantities similar to the extraction of methylene chloride was the use of fibres coated with a combination of nonpolar material. SPME fibre assembly polydimethylsiloxane/divinylbenzene (PDMS/DVB) was most suitable for the extraction of the products mixture obtained after biotransformation of acetylcyclohexane and acetophenone. On the other hand, the best results were obtained for 2-acetylthiophene, α,α,α-trifluoroacetophenone and their derivatives using divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) fibre. In addition, our study showed that Alternaria alternata is a good biocatalyst for bioreduction of ketones to alcohols according to Prelog's rule.
- Ogórek, Rafa?,Jarosz, Bogdan
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- Asymmetric transfer hydrogenation of ketones promoted by manganese(I) pre-catalysts supported by bidentate aminophosphines
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A series of commercially available chiral amino-phosphines, in combination with Mn(CO)5Br, has been evaluated for the asymmetric reduction of ketones, using isopropanol as hydrogen source. With the most selective ligand, the corresponding manga
- Azouzi, Karim,Bruneau-Voisine, Antoine,Vendier, Laure,Sortais, Jean-Baptiste,Bastin, Stéphanie
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- C1-Symmetric PNP Ligands for Manganese-Catalyzed Enantioselective Hydrogenation of Ketones: Reaction Scope and Enantioinduction Model
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A family of ferrocene-based chiral PNP ligands is reported. These tridentate ligands were successfully applied in Mn-catalyzed asymmetric hydrogenation of ketones, giving high enantioselectivities (92%~99% ee for aryl alkyl ketones) as well as high efficiencies (TON up to 2000). In addition, dialkyl ketones could also be hydrogenated smoothly. Manganese intermediates that might be involved in the catalytic cycle were analyzed. DFT calculation was carried out to help understand the chiral induction model. The Mn/PNP catalyst could discriminate two groups with different steric properties by deformation of the phosphine moiety in the flexible 5-membered ring.
- Zeng, Liyao,Yang, Huaxin,Zhao, Menglong,Wen, Jialin,Tucker, James H. R.,Zhang, Xumu
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p. 13794 - 13799
(2020/11/30)
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- A Hammett Study of Clostridium acetobutylicum Alcohol Dehydrogenase (CaADH): An Enzyme with Remarkable Substrate Promiscuity and Utility for Organic Synthesis
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Described is a physical organic study of the reduction of three sets of carbonyl compounds by the NADPH-dependent enzyme Clostridium acetobutylicum alcohol dehydrogenase (CaADH). Previous studies in our group have shown this enzyme to display broad substrate promiscuity, yet remarkable stereochemical fidelity, in the reduction of carbonyl compounds, including α-, β- and γ-keto esters (d -stereochemistry), as well as α,α-difluorinated-β-keto phosphonate esters (l -stereochemistry). To better mechanistically characterize this promising dehydrogenase enzyme, we report here the results of a Hammett linear free-energy relationship (LFER) study across three distinct classes of carbonyl substrates; namely aryl aldehydes, aryl β-keto esters and aryl trifluoromethyl ketones. Rates are measured by monitoring the decrease in NADPH fluorescence at 460 nm with time across a range of substrate concentrations for each member of each carbonyl compound class. The resulting v 0 versus [S] data are subjected to least-squares hyperbolic fitting to the Michaelis-Menton equation. Hammett plots of log(V max) versus σ X yield the following Hammett parameters: (i) for p -substituted aldehydes, ρ = 0.99 ± 0.10, ρ = 0.40 ± 0.09; two domains observed, (ii) for p -substituted β-keto esters ρ = 1.02 ± 0.31, and (iii) for p -substituted aryl trifluoromethyl ketones ρ = -0.97 ± 0.12. The positive sign of ρ indicated for the first two compound classes suggests that the hydride transfer from the nicotinamide cofactor is at least partially rate-limiting, whereas the negative sign of ρ for the aryl trifluoromethyl ketone class suggests that dehydration of the ketone hydrate may be rate-limiting for this compound class. Consistent with this notion, examination of the 13 C NMR spectra for the set of p -substituted aryl trifluo romethyl ketones in 2percent aqueous DMSO reveals significant formation of the hydrate (gem -diol) for this compound family, with compounds bearing the more electron-withdrawing groups showing greater degrees of hydration. This work also presents the first examples of the CaADH-mediated reduction of aryl trifluoromethyl ketones, and chiral HPLC analysis indicates that the parent compound α,α,α-trifluoroacetophenone is enzymatically reduced in 99percent ee and 95percent yield, providing the (S)-stereoisomer, suggesting yet another compound class for which this enzyme displays high enantioselectivity.
- Berkowitz, David B.,Kudalkar, Gaurav P.,Lee, Joshua D.,Tiwari, Virendra K.
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supporting information
p. 237 - 247
(2020/02/18)
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- Asymmetric Catalytic Meerwein-Ponndorf-Verley Reduction of Ketones with Aluminum(III)-VANOL Catalysts
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We report herein an efficient aluminum-catalyzed asymmetric MPV reduction of ketones with broad substrate scope and excellent yields and enantiomeric inductions. A variety of aromatic (both electron-poor and electron-rich) and aliphatic ketones were converted to chiral alcohols in good yields with high enantioselectivities (26 examples, 70-98percent yield and 82-99percent ee). This method operates under mild conditions (-10 °C) and low catalyst loading (1-5 mol percent). Furthermore, this process is catalyzed by the earth-abundant main-group element aluminum and employs 2-propanol as the hydride source.
- Guan, Yong,Mohammadlou, Aliakbar,Staples, Richard,Sullivan, Ryan P.,Wulff, William D.,Yin, Xiaopeng,Zheng, Li
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p. 7188 - 7194
(2020/07/21)
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- Asymmetric Synthesis of Primary and Secondary β-Fluoro-arylamines using Reductive Aminases from Fungi
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The synthesis of chiral amines is of central importance to pharmaceutical chemistry, and the inclusion of fluorine atoms in drug molecules can both increase potency and slow metabolism. Optically enriched β-fluoroamines can be obtained by the kinetic resolution of racemic amines using amine transaminases (ATAs), but yields are limited to 50 %, and also secondary amines are not accessible. In order to overcome these limitations, we have applied NADPH-dependent reductive aminase enzymes (RedAms) from fungal species to the reductive amination of α-fluoroacetophenones with ammonia, methylamine and allylamine as donors, to yield β-fluoro primary or secondary amines with >90 % conversion and between 85 and 99 % ee. In addition, the effect of the progressive introduction of fluorine atoms to the α-position of the acetophenone substrate reveals the effect of mono-, di- and tri-fluorination on the proportion of amine and alcohol in product mixtures, shedding light on the promiscuous ability of imine reductase (IRED)-type dehydrogenases to reduce fluorinated acetophenones to alcohols.
- González-Martínez, Daniel,Cuetos, Aníbal,Sharma, Mahima,García-Ramos, Marina,Lavandera, Iván,Gotor-Fernández, Vicente,Grogan, Gideon
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p. 2421 - 2425
(2020/03/25)
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- Highly Enantioselective Transfer Hydrogenation of Prochiral Ketones Using Ru(II)-Chitosan Catalyst in Aqueous Media
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Unprecedentedly high enantioselectivities are obtained in the transfer hydrogenation of prochiral ketones catalyzed by a Ru complex formed in situ with chitosan chiral ligand. This biocompatible, biodegradable chiral polymer obtained from the natural chitin afforded good, up to 86 % enantioselectivities, in the aqueous-phase transfer hydrogenation of acetophenone derivatives using HCOONa as hydrogen donor. Cyclic ketones were transformed in even higher, over 90 %, enantioselectivities, whereas further increase, up to 97 %, was obtained in the transfer hydrogenations of heterocyclic ketones. The chiral catalyst precursor prepared ex situ was examined by scanning electron microscopy, FT-mid- and -far-IR spectroscopy. The structure of the in situ formed catalyst was investigated by 1H NMR spectroscopy and using various chitosan derivatives. It was shown that a Ru pre-catalyst is formed by coordination of the biopolymer to the metal by amino groups. This precursor is transformed in water insoluble Ru-hydride complex following hydrogen donor addition. The practical value of the developed method was verified by preparing over twenty chiral alcohols in good yields and optical purities. The catalyst was applied for obtaining optically pure chiral alcohols at gram scale following a single crystallization.
- Sz?ll?si, Gy?rgy,Kolcsár, Vanessza Judit
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p. 820 - 830
(2018/12/13)
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- Chiral (cyclopentadienone)iron complexes with a stereogenic plane as pre-catalysts for the asymmetric hydrogenation of polar double bonds
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In this paper, we describe a small library of easy-to-prepare chiral (cyclopentadienone)iron pre-catalysts for enantioselective C[dbnd]O and C[dbnd]N hydrogenations. Starting from readily accessible achiral materials, six chiral (cyclopentadienone)iron complexes (1a-f) possessing a stereogenic plane were synthesized in racemic form. Based on the screening of pre-catalysts (±)-1a-f in the hydrogenation of ketones and ketimines, we selected two complexes (1a and 1d) for resolution by semipreparative enantioselective HPLC. The absolute configuration of the separated enantiomers of 1a and 1d was assigned by XRD analysis (1a) and by comparison between experimental and DFT-calculated ECD and ORD spectra (1d). The enantiopure pre-catalysts (S)-1a and (R)-1d were tested in the asymmetric hydrogenation of several ketones and ketimines and showed good activity and modest enantioselectivity, the e.e. values ranging from very low to moderate (54%).
- Bai, Xishan,Cettolin, Mattia,Mazzoccanti, Giulia,Pierini, Marco,Piarulli, Umberto,Colombo, Valentina,Dal Corso, Alberto,Pignataro, Luca,Gennari, Cesare
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p. 1415 - 1424
(2019/02/09)
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- Asymmetric Hydrogenation of Aryl Perfluoroalkyl Ketones Catalyzed by Rhodium(III) Monohydride Complexes Bearing Josiphos Ligands
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The asymmetric hydrogenation of 2,2,2-trifluoroacetophenones and aryl perfluoroalkyl ketones was developed using a unique, well-defined chloride-bridged dinuclear rhodium(III) complex bearing Josiphos-type diphosphine ligands. These complexes were prepared from [RhCl(cod)]2, Josiphos ligands, and hydrochloric acid. As catalyst precursors, they allow for the efficient and enantioselective synthesis (up to 99 % ee) of chiral secondary alcohols with perfluoroalkyl groups. This system does not require an activating base for the hydrogenation of 2,2,2-trifluoroacetophenones. Additionally, the enantioselective C=O hydrogenations of 2-phenyl-3-(haloacetyl)-indoles, a class of privileged structures in medicinal chemistry, is reported for the first time.
- Brüning, Fabian,Nagae, Haruki,K?ch, Daniel,Mashima, Kazushi,Togni, Antonio
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supporting information
p. 10818 - 10822
(2019/07/31)
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- Chemoenzymatic Synthesis of an Odanacatib Precursor through a Suzuki-Miyaura Cross-Coupling and Bioreduction Sequence
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A series of 1-aryl-2,2,2-trifluoroethanones has been chemically synthesized to later study their bioreduction using stereocomplementary alcohol dehydrogenases (ADHs). Satisfyingly, (R)-alcohols were obtained in high conversions and selectivities using the ADH from Ralstonia species and the one from Rhodococcus ruber, while the (S)-enantiomers were independently produced using the ADH from Lactobacillus brevis and the commercially available evo-1.1.200. In the search for a stereoselective route towards the Odanacatib, an orally bioavailable and selective inhibitor of Cathepsin K, the development of a sequential methodology combining a palladium-catalyzed cross coupling between 1-(4-bromophenyl)-2,2,2-trifluoroethanone and 4-(methylsulfonyl)phenylboronic acid in aqueous medium with the bioreduction of the resulting 2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethanone has been extensively studied. Finally, the desired (R)-2,2,2-trifluoro-1-(4′-(methylsulfonyl)-[1,1′-biphenyl]-4-yl)ethanol was obtained in enantiomerically pure form and 85 % yield with a 128 g L?1 d?1 productivity following a sequential approach.
- González-Martínez, Daniel,Gotor, Vicente,Gotor-Fernández, Vicente
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p. 5800 - 5807
(2019/11/05)
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- HEME PROTEIN CATALYSTS FOR CARBON-BORON BOND FORMATION IN VITRO AND IN VIVO
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Provided herein are methods for producing an organoboron product. The methods include combining a boron-containing reagent and a carbene precursor in the presence of a heme protein, e.g., a cytochrome c, a cytochrome P450, a globin, a protoglobin, a nitric oxide dioxygenase, a peroxidase, or a catalase, or a variant thereof, under conditions sufficient to form the organoboron product. Reaction mixtures for producing organoboron products are also described, as well as whole-cell catalysts comprising heme proteins and variants thereof for forming carbon-boron bonds.
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Paragraph 0028; 0267; 0269
(2018/09/28)
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- Synthesis of new C3 symmetric amino acid- and aminoalcohol-containing chiral stationary phases and application to HPLC enantioseparations
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We recently reported a new C3-symmetric (R)-phenylglycinol N-1,3,5-benzenetricarboxylic acid-derived chiral high-performance liquid chromatography (HPLC) stationary phase (CSP 1) that demonstrated better results as compared to a previously described N-3,5-dintrobenzoyl (DNB) (R)-phenylglycinol-derived CSP. Over a decade ago, (S)-leucinol, (R)-phenylglycine, and (S)-leucine derivatives were used as the starting materials of 3,5-DNB-based Pirkle-type CSPs for chiral separation. In this study, three new C3-symmetric CSPs (CSP 2, 3, and 4) were prepared by combining the ideas and results mentioned above. Here we describe the synthetic procedures and applications of the new C3-symmetric CSPs (CSP 2–CSP 4).
- Yu, Jeongjae,Armstrong, Daniel W.,Ryoo, Jae Jeong
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- Acylative Kinetic Resolution of Alcohols Using a Recyclable Polymer-Supported Isothiourea Catalyst in Batch and Flow
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A polystyrene-supported isothiourea catalyst, based on the homogeneous catalyst HyperBTM, has been prepared and used for the acylative kinetic resolution of secondary alcohols. A wide range of alcohols, including benzylic, allylic, and propargylic alcohols, cycloalkanol derivatives, and a 1,2-diol, has been resolved using either propionic or isobutyric anhydride with good to excellent selectivity factors obtained (28 examples, s values up to 600). The catalyst can be recovered and reused by a simple filtration and washing sequence, with no special precautions needed. The recyclability of the catalyst was demonstrated (15 cycles) with no significant loss in either activity or selectivity. The recyclable catalyst was also used for the sequential resolution of 10 different alcohols using different anhydrides with no cross-contamination between cycles. Finally, successful application in a continuous flow process demonstrated the first example of an immobilized Lewis base catalyst used for the kinetic resolution of alcohols in flow.
- Neyyappadath, Rifahath Mon,Chisholm, Ross,Greenhalgh, Mark D.,Rodríguez-Escrich, Carles,Pericàs, Miquel A.,H?hner, Georg,Smith, Andrew D.
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p. 1067 - 1075
(2018/02/14)
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- Proteins as Macromolecular Ligands for Metal-Catalysed Asymmetric Transfer Hydrogenation of Ketones in Aqueous Medium
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Biohybrid catalysts resulting from the dative anchoring of half-sandwich organometallic complexes [M(arene)(H2O)x(Cl)y]n+ (M = RuII, arene = η6-benzene, p-cymene or mesitylene; M = IrIII, RhIII, arene = η5-Cp*; x = 1–3, y = 0–2, n = 0–2) to bovine beta-lactoglobulin (βLG) or hen egg white lysozyme showed unprecedented behaviour. These constructs were shown to catalyse the asymmetric transfer hydrogenation of aryl ketones in water with sodium formate as hydrogen donor at a much faster rate than the complexes alone. Full conversion of the benchmark substrate 2,2,2-trifluoroacetophenone was reached with an ee of 86 % for the most selective biohybrid. Surprisingly, even the crude biohybrid gave a good ee despite the presence of non-protein-bound metal species in the reaction medium. Other aryl ketones were reduced in the same way, and the highest ee was obtained for ortho-substituted acetophenone derivatives. Furthermore, treatment of βLG with dimethyl pyrocarbonate resulted in a noticeable decrease of the activity and selectivity of the biohybrid, indicating that the sole accessible histidine residue (His146) was probably involved in the coordination and activation of Ru(benzene). This work underscores that protein scaffolds are efficient chiral ligands for asymmetric catalysis. The use of sodium formate instead of dihydrogen makes this approach safe, inexpensive and environmentally friendly.
- de Jesús Cázares-Marinero, José,Przybylski, Cédric,Salmain, Michèle
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p. 1383 - 1393
(2018/04/06)
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- Molecular Basis for the High Activity and Enantioselectivity of the Carbonyl Reductase from Sporobolomyces salmonicolor toward α-Haloacetophenones
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In an effort to develop a practical method for the synthesis of optically pure 2,2,2-trifluoro-1-phenylethanol, we found that the carbonyl reductase (SSCR) from Sporobolomyces salmonicolor showed excellent activity and enantioselectivity toward the halogenated acetophenones. Especially, SSCR exhibited more than 1000 times higher activity toward α,α,α-trifluoroacetophenone than unsubstituted acetophenone, a strikingly different observation from the previously well-studied alcohol dehydrogenase (LBADH) from Lactobacillus brevis. Enzyme-substrate docking and site-directed mutagenesis studies revealed the molecular basis for the high enzyme activity and enantioselectivity of SSCR toward the α-halogenated acetophenones. The hydrogen bond of the Asn207 side chain with the substrate halogen atom and the XH/π interaction of the substrate phenyl group with the side chains of Ser222/Thr223 resulted in the formation of the highly reactive conformation of α-halogenated acetophenones in the active site of the enzyme. (S)-2,2,2-Trifluoro-1-phenylethanol was prepared in excellent isolated yield and enantiomeric excess from the reduction of α,α,α-trifluoroacetophenone with mutant T209A. These results suggest that tuning the interactions between the halogen atoms/phenyl group of the substrate and the amino acid residues of the enzyme would lead to valuable mutants for the practical synthesis of β-haloalcohols.
- Chen, Xi,Zhang, Hongliu,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
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p. 3525 - 3531
(2018/04/14)
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- Accessible Bifunctional Oxy-Tethered Ruthenium(II) Catalysts for Asymmetric Transfer Hydrogenation
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A concise synthesis of new oxy-tethered ruthenium complexes effective for the asymmetric transfer hydrogenation of aromatic ketones is described. The oxy-tether was constructed via a defluorinative etherification arising from an intramolecular nucleophilic substitution of a perfluorinated phenylsulfonyl substituent. The obtained tethered complexes exhibited desirable catalytic activity and selectivity, especially in the asymmetric transfer hydrogenation of functionalized aromatic ketones. The robustness and rigidity of the tether contribute to their superior catalytic performance relative to the nontethered prototype complex.
- Matsunami, Asuka,Ikeda, Marika,Nakamura, Hitomi,Yoshida, Minori,Kuwata, Shigeki,Kayaki, Yoshihito
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supporting information
p. 5213 - 5218
(2018/09/13)
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- Genetically programmed chiral organoborane synthesis
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Recent advances in enzyme engineering and design have expanded nature's catalytic repertoire to functions that are new to biology1-3. However, only a subset of these engineered enzymes can function in living systems4-7. Finding enzymatic pathways that form chemical bonds that are not found in biology is particularly difficult in the cellular environment, as this depends on the discovery not only of new enzyme activities, but also of reagents that are both sufficiently reactive for the desired transformation and stable in vivo. Here we report the discovery, evolution and generalization of a fully genetically encoded platform for producing chiral organoboranes in bacteria. Escherichia coli cells harbouring wild-type cytochrome c from Rhodothermus marinus8 (Rma cyt c) were found to form carbon-boron bonds in the presence of borane-Lewis base complexes, through carbene insertion into boron-hydrogen bonds. Directed evolution of Rma cyt c in the bacterial catalyst provided access to 16 novel chiral organoboranes. The catalyst is suitable for gram-scale biosynthesis, providing up to 15,300 turnovers, a turnover frequency of 6,100 h-1, a 99:1 enantiomeric ratio and 100% chemoselectivity. The enantiopreference of the biocatalyst could also be tuned to provide either enantiomer of the organoborane products. Evolved in the context of whole-cell catalysts, the proteins were more active in the whole-cell system than in purified forms. This study establishes a DNA-encoded and readily engineered bacterial platform for borylation; engineering can be accomplished at a pace that rivals the development of chemical synthetic methods, with the ability to achieve turnovers that are two orders of magnitude (over 400-fold) greater than those of known chiral catalysts for the same class of transformation9-11. This tunable method for manipulating boron in cells could expand the scope of boron chemistry in living systems.
- Jennifer Kan,Huang, Xiongyi,Gumulya, Yosephine,Chen, Kai,Arnold, Frances H.
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p. 132 - 136
(2018/03/28)
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- Synthetically useful variants of industrial lipases from: Burkholderia cepacia and Pseudomonas fluorescens
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Industrial enzymes lipase PS (LPS) and lipase AK (LAK), which originate from Burkholderia cepacia and Pseudomonas fluorescens, respectively, are synthetically useful biocatalysts. To strengthen their catalytic performances, we introduced two mutations into hot spots of the active sites (residues 287 and 290). The LPS-L287F/I290A double mutant showed high catalytic activity and enantioselectivity for poor substrates for which the wild-type enzyme showed very low activity. The LAK-V287F/I290A double mutant was also an excellent biocatalyst with expanded substrate scope, which was comparable to the LPS-L287F/I290A double mutant. Thermodynamic parameters were determined to address the origin of the high enantioselectivity of the double mutant. The ΔΔH? term, but not the ΔΔS? term, was predominant, which suggests that the enantioselectivity is driven by a differential energy associated with intermolecular interactions around Phe287 and Ala290. A remarkable solvent effect was observed, giving a bell-shaped profile between the E values and the log&P or ? values of solvents with the highest E value in i-Pr2O. This suggests that an organic solvent with appropriate hydrophobicity and polarity provides the double mutant with some flexibility that is essential for excellent catalytic performance.
- Yoshida, Kazunori,Ono, Masakazu,Yamamoto, Takahiro,Utsumi, Takashi,Koikeda, Satoshi,Ema, Tadashi
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supporting information
p. 8713 - 8719
(2017/11/03)
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- Efficient Synthesis of (R)-2-Chloro-1-(2,4-dichlorophenyl)ethanol with a Ketoreductase from Scheffersomyces stipitis CBS 6045
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By enzyme screening, a ketoreductase cloned from Scheffersomyces stipitis CBS 6045 and named SsCR was identified that could catalyze the asymmetric hydrogenation of a variety of aromatic ketones. SsCR exhibited a specific activity of 65 U mg?1p
- Shang, Yue-Peng,Chen, Qi,Kong, Xu-Dong,Zhang, Yu-Jun,Xu, Jian-He,Yu, Hui-Lei
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supporting information
p. 426 - 431
(2017/02/10)
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- Asymmetric Ketone Reduction by Imine Reductases
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The rapidly growing area of asymmetric imine reduction by imine reductases (IREDs) has provided alternative routes to chiral amines. Here we report the expansion of the reaction scope of IREDs by showing the stereoselective reduction of 2,2,2-trifluoroacetophenone. Assisted by an in silico analysis of energy barriers, we evaluated asymmetric hydrogenations of carbonyls and imines while considering the influence of substrate reactivity on the chemoselectivity of this novel class of reductases. We report the asymmetric reduction of C=N as well as C=O bonds catalysed by members of the IRED enzyme family.
- Lenz, Maike,Meisner, Jan,Quertinmont, Leann,Lutz, Stefan,K?stner, Johannes,Nestl, Bettina M.
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p. 253 - 256
(2017/02/15)
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- Catalytic asymmetric Meerwein-Ponndorf-Verley reduction of glyoxylates induced by a chiral N,N′-dioxide/Y(OTf)3 complex
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An asymmetric Meerwein-Ponndorf-Verley (MPV) reduction of glyoxylates was for the first time accomplished via an N,N′-dioxide/Y(OTf)3 complex with aluminium alkoxide and molecular sieves (MSs) as crucial additives. A variety of optically active α-hydroxyesters were obtained with excellent results. A possible reaction mechanism was proposed based on the experiments.
- Wu, Wangbin,Zou, Sijia,Lin, Lili,Ji, Jie,Zhang, Yuheng,Ma, Baiwei,Liu, Xiaohua,Feng, Xiaoming
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supporting information
p. 3232 - 3235
(2017/03/20)
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- Chiral terpene auxiliaries IV: new monoterpene PHOX ligands and their application in the catalytic asymmetric transfer hydrogenation of ketones
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New PHOX ligands, derived in three steps from (1R, 2S, 3R, 5R)-3-amino-apopinan-2-ol 1 and (1R, 2R, 3S, 5R)-3-amino-pinan-2-ol 2 were applied as chiral ligands for the formation of ruthenium catalysts. The catalysts were used in asymmetric transfer hydrogenations of prochiral ketones producing the corresponding alcohols in moderate to high yields and enantioselectivity.
- Kmieciak, Anna,Krzemiński, Marek P.
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p. 467 - 472
(2017/03/24)
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- Alkaloid-induced asymmetric hydrogenation on bimetallic Pt@Cu cathodes under electrochemical conditions
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Bimetallic Pt@Cu nanoparticles (NPs) with low Pt loading obtained by reducing platinum precursors on Cu NPs were coated on carbon paper and used as a cathode for asymmetric hydrogenation by the electrochemical method. The Pt@Cu NPs exhibited enhanced cata
- Yue, Ying-Na,Wu, Di,Zeng, Sheng,Yang, Man-Ping,Wang, Huan,Lu, Jia-Xing
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p. 7853 - 7856
(2017/08/14)
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- Asymmetric Reduction of Prochiral Ketones by Using Self-Sufficient Heterogeneous Biocatalysts Based on NADPH-Dependent Ketoreductases
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The development of cell-free and self-sufficient biocatalytic systems represents an emerging approach to address more complex synthetic schemes under nonphysiological conditions. Herein, we report the development of a self-sufficient heterogeneous biocatalyst for the synthesis of chiral alcohols without the need to add an exogenous cofactor. In this work, an NADPH-dependent ketoreductase was primarily stabilized and further co-immobilized with NADPH to catalyze asymmetric reductions without the addition of an exogenous cofactor. As a result, the immobilized cofactor is accessible, and thus, it is recycled inside the porous structure without diffusing out into the bulk, as demonstrated by single-particle in operando studies. This self-sufficient heterogeneous biocatalyst was used and recycled for the asymmetric reduction of eleven carbonyl compounds in a batch reactor without the addition of exogenous NADPH to achieve the corresponding alcohols in 100 % yield and >99 % ee; this high performance was maintained over five consecutive reaction cycles. Likewise, the self-sufficient heterogeneous biocatalyst was integrated into a plug flow reactor for the continuous synthesis of one model secondary alcohol, which gave rise to a space-time yield of 97–112 g L?1 day?1; additionally, the immobilized cofactor accumulated a total turnover number of 1076 for 120 h. This is one of the few examples of the successful implementation of continuous reactions in aqueous media catalyzed by cell-free and immobilized systems that integrate both enzymes and cofactors into the solid phase.
- Benítez-Mateos, Ana I.,San Sebastian, Eneko,Ríos-Lombardía, Nicolás,Morís, Francisco,González-Sabín, Javier,López-Gallego, Fernando
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p. 16843 - 16852
(2017/11/16)
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- Novel access to N,N′-diaryl-trans-1,2-diaminocyclohexane ligands. A cheap and easy way to prepare ligand for asymmetric transfer hydrogenation
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N,N′-diaryl-trans-1,2-diaminocyclohexane ligands were prepared from 1,2-diaminocyclohexane and cyclohexanone derivatives via a heterogeneous palladium catalysis. In one step an alkylation followed by an aromatisation is performed under air or in the presence of an hydrogen trap. The interest of the synthesized ligands were evaluated in the reduction of aromatic ketones. The alcohols were efficiently and selectively obtained with an iridium complex and a mixture of formic acid and sodium formate.
- El-Asaad, Bilal,Guicheret, Boris,Métay, Estelle,Karamé, Iyad,Lemaire, Marc
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p. 196 - 202
(2015/11/24)
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- Synthesis of Planar Chiral Shvo Catalysts for Asymmetric Transfer Hydrogenation
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A new type of planar chiral Shvo catalysts, where the chirality is based solely on different substitution flanking the C£O function, was prepared and used for transfer hydrogenation of imines and ketones. The reduction of ketimines represented by N-(1-phe
- Dou, Xiaowei,Hayashi, Tamio
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supporting information
p. 1054 - 1058
(2016/04/19)
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- Fine tuning of molecular and supramolecular properties of simple trianglimines-the role of the functional group
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Chiral, triangular poly-azamacrocycles (trianglimines) readily available from enantiomerically pure trans-1,2-diaminocyclohexane and various aromatic dialdehydes, differ in their nature and substitution pattern. The highly symmetrical macrocycle having two electron-donating groups attached to the aryl moieties is formed under thermodynamic control that fulfilled the so called entropy of symmetry rule. Conversely, from the 2-nitroterephthaldehyde a kinetic product of trivial C1 symmetry is solely obtained, whereas from 2-methoxyterepthaldehyde a mixture of C3- and C1-symmetrical macrocycles are formed. The factors that contribute to the mechanism of the macrocycle formation were determined on the basis of an experimental/theoretical approach. The non-symmetrical structure of the macrocycle resulted from a symmetrical intermediate that appeared during cyclocondensation. The chiroptical properties of the trianglimines were studied by means of experimental ECD and VCD methods supported by quantum-chemical calculations. The nitro-substituted trianglimine appeared to be a simple, low molecular weight supergelator forming in polar media of stable chiral organogels. The structure of the gel is affected by the nature and chirality of the dopant. The hexaimine macrocycles after reduction of the CN imine bonds formed trianglamines-useful chiral ligands in stereoselective synthesis. The Zn-trianglamine complexes were employed as catalysts for asymmetric hydrosilylation of prochiral ketones, providing products of enantiomeric excess up to 98%. This remains the best result obtained for Zn-diamine catalysed asymmetric hydrosilylation of ketones so far.
- Gajewy,Szymkowiak,Kwit
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p. 53358 - 53369
(2016/06/14)
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- A series of novel β-hydroxyamide based catalysts for borane-mediated enantioselective reductions of prochiral ketones: Dedicated to Professor Halil Hosgoren on the occasion of his 66th birthday
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The enantioselective reduction of prochiral ketones with borane in the presence of a chiral ligand has received considerable attention. Hydroxylamine-based chiral ligands with amide and hydroxyl functions in the presence of other co-ordinating groups are highly effective in these asymmetric reductions. The current work presents a simple one step synthesis of a series of β-hydroxyamide-based ligands from the reaction between 3-hydroxy-2-naphthoic acid and chiral amino alcohols and their applications as catalysts in asymmetric borane-mediated reductions of aromatic prochiral ketones in THF. The reductions provided the corresponding secondary alcohols with up to 96% ee and in good to excellent yields (89–99%). DFT calculations at B3LYP/6-31+g(d) level offered theoretical models to account for the enantioselectivity imposed by the chiral ligands in the reductions of the ketones.
- Azizoglu, Murat,Erdogan, Asl?,Arslan, Nevin,Turgut, Y?lmaz,Hosgoren, Halil,Pirinccioglu, Necmettin
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p. 614 - 622
(2016/07/12)
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- Enantioselective hydrogenation of ketones by iridium nanoparticles ligated with chiral secondary phosphine oxides
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Chiral iridium nanoparticles (IrNPs) were synthesized by H2 reduction of (1,5-cyclooctadiene)(methoxy)iridium(i) dimer ([Ir(OMe)(COD)]2) in the presence of an asymmetric secondary phosphine oxide (4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′
- Cano, Israel,Tschan, Mathieu J.-L.,Martínez-Prieto, Luis M.,Philippot, Karine,Chaudret, Bruno,Van Leeuwen, Piet W.N.M.
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p. 3758 - 3766
(2016/06/14)
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- Third-Generation Amino Acid Furanoside-Based Ligands from d-Mannose for the Asymmetric Transfer Hydrogenation of Ketones: Catalysts with an Exceptionally Wide Substrate Scope
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A modular ligand library of α-amino acid hydroxyamides and thioamides was prepared from 10 different N-tert-butyloxycarbonyl-protected α-amino acids and three different amino alcohols derived from 2,3-O-isopropylidene-α-d-mannofuranoside. The ligand library was evaluated in the half-sandwich ruthenium- and rhodium-catalyzed asymmetric transfer hydrogenation of a wide array of ketone substrates, including simple as well as sterically demanding aryl alkyl ketones, aryl fluoroalkyl ketones, heteroaromatic alkyl ketones, aliphatic, conjugated and propargylic ketones. Under the optimized reaction conditions, secondary alcohols were obtained in high yields and in enantioselectivities up to >99%. The choice of ligand/catalyst allowed for the generation of both enantiomers of the secondary alcohols, where the ruthenium-hydroxyamide and the rhodium-thioamide catalysts act complementarily towards each other. The catalytic systems were also evaluated in the tandem isomerization/asymmetric transfer hydrogenation of racemic allylic alcohols to yield enantiomerically enriched saturated secondary alcohols in up to 98% ee. Furthermore, the catalytic tandem α-alkylation/asymmetric transfer hydrogenation of acetophenones and 3-acetylpyridine with primary alcohols as alkylating and reducing agents was studied. Secondary alcohols containing an elongated alkyl chain were obtained in up to 92% ee. (Figure presented.).
- Margalef, Jèssica,Slagbrand, Tove,Tinnis, Fredrik,Adolfsson, Hans,Diéguez, Montserrat,Pàmies, Oscar
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p. 4006 - 4018
(2016/12/30)
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- Reconstruction of the Catalytic Pocket and Enzyme–Substrate Interactions To Enhance the Catalytic Efficiency of a Short-Chain Dehydrogenase/Reductase
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To upgrade the short-chain dehydrogenase/reductase EbSDR8 to a powerful tool for the synthesis of antiPrelog chiral alcohols, rational design was performed by reconstructing the catalytic pocket and enzyme–substrate interactions. The resulting variants showed significantly improved catalytic efficiency (kcat/KM; kcat=turnover rate, KM=Michaelis constant) towards a series of prochiral ketones, with kcat/KM values more than 15-fold greater than that of wildtype EbSDR8 in some cases. More importantly, none of the mutations caused an adverse effect on the stereoselectivity. The increased steric repulsion and the C?H???π interaction involving the alkyl side chain of L153 and the phenyl ring of the substrate turned out to be crucial factors connected to the enhanced enzymatic activity. This provided new insight into the role of steric hindrance and non canonical interactions in protein engineering. Furthermore, the recombinant E. coli whole cells expressing the EbSDR8 variant G94A/S153L successfully catalyzed the reduction of a high-concentration 2,2,2-trifluoroacetophenone. The results demonstrated the effectiveness of rational design and the applicability of the designed variants in the efficient reduction of prochiral ketones.
- Li, Aipeng,Ye, Lidan,Yang, Xiaohong,Wang, Bei,Yang, Chengcheng,Gu, Jiali,Yu, Hongwei
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p. 3229 - 3233
(2016/10/24)
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- Chemo- and Enantioselective Addition and β-Hydrogen Transfer Reduction of Carbonyl Compounds with Diethylzinc Reagent in One Pot Catalyzed by a Single Chiral Organometallic Catalyst
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Using a single chiral phosphoramide-Zn(II) complex as the catalyst, the asymmetric β-H transfer reduction of aromatic α-trifluoromethyl ketones and enantioselective addition of aromatic aldehydes with Et2Zn in one pot were successfully realized, affording the corresponding additive products of secondary alcohols in high yields (up to 99%) with excellent enantioselectivities (up to 98% ee) and the reduction products of α-trifluoromethyl alcohols in good to excellent yields with up to 77% ee.
- Huang, Huayin,Zong, Hua,Bian, Guangling,Song, Ling
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p. 12614 - 12619
(2016/01/09)
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- Biocatalytic anti-Prelog reduction of prochiral ketones with whole cells of a newly isolated strain Empedobacter brevis ZJUY-1401
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Robust biocatalysts are in high demand for the reduction of prochiral ketones to anti-Prelog chiral alcohols. A recently isolated bacterial strain ZJUY-1401 exhibited high reduction activity and excellent anti-Prelog stereospecificity toward prochiral ketones. Based on the colony and microscopic morphology, physiological tests, and 16S rDNA sequence, the isolate was identified as Empedobacter brevis. Upon addition of either NADH or NADPH, the whole cells of E. brevis ZJUY-1401 showed enhanced catalytic activity. The activity and stereoselectivity of the biocatalyst toward acetophenone were significantly increased in the presence of 10% (v/v) ethanol as cosubstrate. Important properties concerning the application of E. brevis ZJUY-1401 include the excellent catalytic performance over a broad pH range from 6.0 to 9.5, temperature optimum of 35 °C, and noticeable tolerance against ethanol. Under the optimal conditions, E. brevis ZJUY-1401 was highly active for the reduction of acetophenone derivatives, giving corresponding alcohols in excellent enantiomeric purity (>99% ee). These results imply that E. brevis ZJUY-1401 is a promising biocatalyst for the preparation of anti-Prelog chiral alcohols.
- Li, Aipeng,Ye, Lidan,Guo, Fei,Yang, Xiaohong,Yu, Hongwei
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- Catalytic asymmetric β-hydrogen transfer reduction of α-trifluoromethyl aromatic ketones with diethylzinc
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Abstract The catalytic asymmetric β-hydrogen transfer reduction of α-trifluoromethyl ketones using diethylzinc as the β-hydrogen donor was developed with the use of phosphinamide chiral ligand. The corresponding alcohol products were afforded in good yields with up to 73% ee. This method was successfully applied to the chemo- and enantioselective reduction of α-methyl/trifluoromethyl diketone, affording 88% yield and 70% ee of the fluorinated hydroxylketone product.
- Huang, Huayin,Zong, Hua,Bian, Guangling,Song, Ling
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p. 835 - 839
(2015/08/18)
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- Chiral imidazolidinone and proline-derived surface modifiers for the Pt-catalysed asymmetric hydrogenation of activated ketones
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A series of imidazolidinone and proline derivatives have been synthesised and tested with regard to their suitability for the chiral modification of platinum used for the asymmetric hydrogenation of activated ketones. Hydrogenations of ketopantolactone (KPL), methyl benzoylformate (MBF) and trifluoroacetophenone (TFAP) performed at low hydrogen pressures (1 and 10 bar) were selected as test reactions. With some of these synthethic modifiers, encouraging levels of enantioselectivity were achieved (up to 73.5:26.5 e.r.) without optimisation of the reaction conditions. Moreover, performance enhancement of l-proline derived-modifiers, as a consequence of molecular editing with fluorine, was found to be significant (OH → F, Δee up to 23%) contributing to the growing interest in modulating catalyst performance by fluorine introduction.
- Holland, Mareike C.,Meemken, Fabian,Baiker, Alfons,Gilmour, Ryan
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p. 335 - 345
(2015/02/19)
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- Synthesis of a P-stereogenic PNPtBu,Ph ruthenium pincer complex and its application in asymmetric reduction of ketones
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A novel P-stereogenic PNPtBu,Ph ruthenium complex has been synthesized and characterized enabling the asymmetric hydrogenation of a wide range of aromatic ketones with excellent catalytic activities (up to 98% conversion) and good levels of enantiodiscrimination (up to 95% ee). P-stereogenic PNPtBu,Ph Ru complex was for the first time synthesized and characterized and has proven to be an efficient catalyst for the asymmetric reduction of a wide range of ketones
- Arenas, Ismael,Boutureira, Omar,Matheu, M. Isabel,Díaz, Yolanda,Castillón, Sergio
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supporting information
p. 3666 - 3669
(2015/06/16)
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- Chiral terpene auxiliaries III: Spiroborate esters from (1R,2S,3R,5R)-3-amino-apopinan-2-ol as highly effective catalysts for asymmetric reduction of ketones with borane
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New spiroborate esters, derived from terpene amino alcohols, (S)-prolinol, and 2-aminoethanol, were employed as catalysts in the borane reduction of acetophenone and other aryl alkyl and halogenated ketones. The corresponding alcohols were obtained in high yields and with enantioselectivities up to 98% ee. The influence of the amino alcohol and the diol moieties of spiroborate on the reaction selectivity was examined. The catalyst load, the nature of the solvent, the borane source, and the reaction conditions were also investigated.
- ?wiklińska, Marta,Krzemiński, Marek P.,Tafelska-Kaczmarek, Agnieszka
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p. 1453 - 1458
(2015/12/09)
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- Enantioselective bioreductive preparation of chiral halohydrins employing two newly identified stereocomplementary reductases
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Two robust stereocomplementary carbonyl reductases (DhCR and CgCR) were identified through rescreening the carbonyl reductase toolbox. Five reductases were returned through the activity and enantioselectivity assay for α-chloro-1-acetophenone and ethyl 4-chloro-3-oxo-butanate (COBE). Three reductases were stable at elevated substrate loading. Enzymatic characterization revealed that DhCR and CgCR were more thermostable. As much as 330 g COBE in 1 L biphasic reaction mixture was reduced to (S)- and (R)-3-hydroxy-4-chlorobutyrate by DhCR and CgCR (coexpressed with glucose dehydrogenase), with 92.5% and 93.0% yields, >99% ee, and total turnover numbers of 53800 and 108000, respectively. Six other α-halohydrins were asymmetrically reduced to optically pure forms at a substrate loading of 100 g L-1. Our results indicate the potential of these two stereocomplementary reductases in the synthesis of valuable α-halohydrins for pharmaceuticals. This journal is
- Xu, Guo-Chao,Yu, Hui-Lei,Shang, Yue-Peng,Xu, Jian-He
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p. 22703 - 22711
(2015/03/14)
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- Characterization of an excellent anti-Prelog short-chain dehydrogenase/reductase EbSDR8 from Empedobacter brevis ZJUY-1401
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Empedobacter brevis ZJUY-1401 is capable of producing anti-Prelog alcohols with excellent stereoselectivity. The gene encoding a short-chain dehydrogenase/reductase from E. brevis ZJUY-1401 (EbSDR8) was cloned and heterologously expressed in Escherichia coli, and the purified recombinant protein was characterized. The subunit of EbSDR8 is composed of 250 amino acids with a calculated molecular mass of 26.4 kDa. Important properties regarding the application of EbSDR8 include utilization of cheaper coenzyme, the excellent catalytic performance over a broad pH range from 7.0 to 10.5, and temperature optimum of 35 °C. The enzyme showed moderate thermostability, with half-lives of 4.4 h at 35 °C and 3.1 h at 45 °C, respectively. In the presence of isopropanol as a cosubstrate, the whole-cell of recombinant E. coli expressing EbSDR8 could efficiently catalyze the asymmetric reduction without addition of any NADH into the reaction system. EbSDR8 displayed good activity and excellent stereoselectivity toward a spectrum of acetophenone derivatives, providing anti-Prelog alcohols with >99% ee for the majority of the substrates. These results suggest that EbSDR8 is a powerful chiral tool for the production of anti-Prelog alcohols.
- Li, Aipeng,Ye, Lidan,Wu, Hongping,Yang, Xiaohong,Yu, Hongwei
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p. 179 - 187
(2015/10/12)
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- Identification of key residues in Debaryomyces hansenii carbonyl reductase for highly productive preparation of (S)-aryl halohydrins
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Key residues of Debaryomyces hansenii carbonyl reductase in the determination of the reducing activity towards aryl haloketones were identified through combinatorial mutation of conserved residues. This study provides a green and efficient biocatalyst for the synthesis of (S)-aryl halohydrins.
- Xu, Guo-Chao,Shang, Yue-Peng,Yu, Hui-Lei,Xu, Jian-He
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supporting information
p. 15728 - 15731
(2015/11/02)
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- β-Hydroxyamide-based ligands and their use in the enantioselective borane reduction of prochiral ketones
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Hydroxyamide-based ligands have occupied a considerable place in asymmetric synthesis. Here we report the synthesis of seven β-hydroxyamide-based ligands from the reaction of 2-hydroxynicotinic acid with chiral amino alcohols and test their effect on the enantioselective reduction of aromatic prochiral ketones with borane in tetrahydofuran (THF). They produce the corresponding secondary alcohols with up to 76% enantiomeric excess (ee) and good to excellent yields (86-99%). Chirality 26:21-26, 2013. 2013 Wiley Periodicals, Inc.
- Azizoglu, Murat,Erdogan, Asli,Arslan, Nevin,Turgut, Yilmaz
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- Artificial metalloenzymes derived from bovine β-lactoglobulin for the asymmetric transfer hydrogenation of an aryl ketone-synthesis, characterization and catalytic activity
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A series of diimines derived from saturated and unsaturated fatty acids and including a dipyridylamine (dpa) or a bispyridylmethane (bpm) scaffold as a chelating moiety were synthesized and characterized spectroscopically. Complexation by [LM(μ-Cl)Cl]sub
- Chevalley, Alice,Cherrier, Mickael V.,Fontecilla-Camps, Juan C.,Ghasemi, Mahsa,Salmain, Michele
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supporting information
p. 5482 - 5489
(2014/04/03)
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- Continuous flow whole cell bioreduction of fluorinated acetophenone
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Several microorganism strains were used to reduce 2,2,2- trifluoroacetophenone (1) and 4′-Br-2,2,2-trifluoroacetophenone (3). Immobilized cells of Geotrichum candidum in calcium alginate led to conversion and enantiomeric excess higher than 99%. By using immobilized G. candidum cells under continuous flow conditions, the same conversion and enantiomeric excess were achieved in 90 min of residence time.
- De Oliveira Lopes, Raquel,Ribeiro, Joyce Benzaquem,Silva De Miranda, Amanda,Vieira Da Silva, Gabriela Veloso,Miranda, Leandro S.M.,Ramos Leal, Ivana Corrêa,Mendon?a Alves De Souza, Rodrigo Octavio
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p. 3239 - 3242
(2014/05/06)
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- Modular hydroxyamide and thioamide pyranoside-based ligand library from the sugar pool: New class of ligands for asymmetric transfer hydrogenation of ketones
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A large library of pyranoside-based hydroxyamide and thioamide ligands has been synthesized for asymmetric transfer hydrogenation in an attempt to expand the scope of the substrates to cover a broader range of challenging heteroaromatic and aryl/fluoroalkyl ketones. These ligands have the advantage that they are prepared from commercial D-glucose, D-glucosamine and α-amino acids, inexpensive natural chiral feedstocks. By carefully selecting the ligand components (substituents/configurations at the amide/thioamide moiety, the position of amide/thioamide group and the configuration at C-2), we found that pyranoside-based thioamide ligands provided excellent enantioselectivities (in the best cases, ees of >99% were achieved) in a broad range of ketones, including the less studied heteroaromatics and challenging aryl/fluoroalkyls. Note that both enantiomers of the reduction products can be obtained with excellent enantioselectivities by simply changing the absolute configuration of the thioamide substituent.
- Coll, Mercè,Pàmies, Oscar,Diéguez, Montserrat
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p. 2293 - 2302
(2014/07/21)
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- Monitoring surface processes during heterogeneous asymmetric hydrogenation of ketones on a chirally modified platinum catalyst by operando spectroscopy
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Surface processes occurring at the catalytic chiral surface of a cinchona-modified Pt catalyst during the asymmetric hydrogenation of activated ketones have been monitored for the first time using operando ATR-IR spectroscopy. Fundamental information about this catalytic system could be gained, including the chiral modification process of the catalyst, the surface interaction of reactant ketone with preadsorbed chiral modifier, the role of hydrogen as well as the influence of the product enantiomers in the catalytic cycle. The formation of a diastereomeric transient surface complex between ketone and chiral modifier was found to be related to the ketone consumption. Among the studied activated ketones, a correlation between stereoselection and the strength of the intermolecular hydrogen bond was identified. Dissociated hydrogen from the catalytic surface is found to play a crucial role in the formation of the diastereomeric surface complex.
- Meemken, Fabian,Hungerbuehler, Konrad,Baiker, Alfons
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supporting information
p. 8640 - 8644
(2014/08/18)
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- Synthesis and catalytic applications of an extended range of tethered ruthenium(II)/η6-arene/diamine complexes
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A series of novel enantiopure Ru(II) complexes containing a chiral diamine and η6-arene connected by a tethering group have been prepared and were evaluated in the asymmetric reductions of a range of ketones. Changes to the level of steric hindrance and the addition of an electron-withdrawing functionality on the sulfonyl group have a significant effect on the reactivity and enantioselectivity of the catalysts.
- Hodgkinson, Roy,Jurk, Vclav,Zanotti-Gerosa, Antonio,Nedden, Hans Günter,Blackaby, Andrew,Clarkson, Guy J.,Wills, Martin
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supporting information
p. 5517 - 5524
(2015/02/19)
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- Steric vs. electronic effects in the Lactobacillus brevis ADH-catalyzed bioreduction of ketones
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Lactobacillus brevis ADH (LBADH) is an alcohol dehydrogenase that is commonly employed to reduce alkyl or aryl ketones usually bearing a methyl, an ethyl or a chloromethyl as a small ketone substituent to the corresponding (R)-alcohols. Herein we have tested a series of 24 acetophenone derivatives differing in their size and electronic properties for their reduction employing LBADH. After plotting the relative activity against the measured substrate volumes we observed that apart from the substrate size other effects must be responsible for the activity obtained. Compared to acetophenone (100% relative activity), other small substrates such as propiophenone, α,α, α-trifluoroacetophenone, α-hydroxyacetophenone, and benzoylacetonitrile had relative activities lower than 30%, while medium-sized ketones such as α-bromo-, α,α-dichloro-, and α,α-dibromoacetophenone presented relative activities between 70% and 550%. Moreover, the comparison between the enzymatic activity and the obtained final conversions using an excess or just 2.5 equiv. of the hydrogen donor 2-propanol, denoted again deviations between them. These data supported that these hydrogen transfer (HT) transformations are mainly thermodynamically controlled. For instance, bulky α-halogenated derivatives could be quantitatively reduced by LBADH even employing 2.5 equiv. of 2-propanol independently of their kinetic values. Finally, we found good correlations between the IR absorption band of the carbonyl groups and the degrees of conversion obtained in these HT processes, making this simple method a convenient tool to predict the success of these transformations. The Royal Society of Chemistry.
- Rodriguez, Cristina,Borzecka, Wioleta,Sattler, Johann H.,Kroutil, Wolfgang,Lavandera, Ivan,Gotor, Vicente
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supporting information
p. 673 - 681
(2014/01/06)
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- A solar light-driven, eco-friendly protocol for highly enantioselective synthesis of chiral alcohols via photocatalytic/biocatalytic cascades
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The judicious utilization of solar light for the asymmetric synthesis of optically active compounds by imitating natural photosynthesis introduces a new concept that harnesses this renewable energy in vitro for ultimate transformation into chiral chemical bonds. Herein, we present a comprehensive description of such a biomimetic endeavor towards the design and construction of an asymmetric artificial photosynthesis system that comprises an efficient method of nicotinamide cofactor (NADPH) regeneration under visible light employing a graphene-based light harvesting photocatalyst and its subsequent utilization in an enzyme-catalyzed asymmetric reduction of prochiral ketones to expediently furnish the corresponding chiral secondary alcohols. A detailed optimization study revealed a major dependency of the reaction outcome on the amount of cofactor, photocatalyst and enzyme used, as well as the mode of their addition. A series of structurally diverse ketones bearing an array of (hetero)aryl/alkyl substituents proved to be highly suitable to our photocatalytic-biocatalytic cascade approach, providing (R/S)-1-(hetero)aryl/ alkylethanols in excellent enantioselectivities (ee ~ 95->99.9%) under mild and environmentally benign conditions. To the best of our knowledge, the synthesis of these enantiopure alcohols employing a visible-light-driven nicotinamide cofactor regeneration strategy has been reported for the first time. Such enantioenriched alcohols act as versatile chiral building blocks for the synthesis of compounds having industrial and pharmaceutical relevance. In addition, this solar-to-chiral chemicals prototype appears advantageous from ecological and economical perspectives. We describe mechanistic pathways to demonstrate how the present catalytic synthesis protocol functions through perfect orchestration between visible-light-driven photocatalysis and biocatalysis to be successively applied in inducing asymmetry in an achiral molecule for the ultimate goal of solar energy utilization in the synthesis of valuable chiral fine chemicals. This work highlights the potential advantages of a bioinspired system to the pertinence of solar energy in asymmetric transformations leading to enantioenriched alcohol precursors, and thus opens up a new field of research that might emerge as an important breakthrough with promising implications towards generating a sustainable and non-fossil/non- nuclear energy future. the Partner Organisations 2014.
- Choudhury, Sumit,Baeg, Jin-Ook,Park, No-Joong,Yadav, Rajesh K.
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supporting information
p. 4389 - 4400
(2014/09/29)
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- The enantioselective trifluoromethylation of aromatic aldehydes by quaternary ammonium bromide and (IPr)CuF at low catalyst loading
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A general catalytic enantioselective trifluoromethylation of aromatic aldehydes using (IPr)CuF and quinidine-derived quaternary ammonium salt as catalysts has been developed. A wide range of aromatic aldehydes are converted to the corresponding products in up to 92% yield and 81% ee at 2 mol% of catalyst loading.
- Wu, Shaoxiang,Guo, Jiyi,Sohail, Muhammad,Cao, Chengyao,Chen, Fu-Xue
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